Reduced Ribose-5-Phosphate Isomerase A-1 Expression in Specific Neurons and Time Points Promotes Longevity in Caenorhabditis elegans

Deregulation of redox homeostasis is often associated with an accelerated aging process. Ribose-5-phosphate isomerase A (RPIA) mediates redox homeostasis in the pentose phosphate pathway (PPP). Our previous study demonstrated that knockdown boosts the healthspan in . However, whether the knockdown of , the ortholog in , can improve the healthspan in remains unknown. Here, we report that spatially and temporally limited knockdown of prolongs lifespan and improves the healthspan in , reflecting the evolutionarily conserved phenotypes observed in . Ubiquitous and pan-neuronal knockdown of both enhance tolerance to oxidative stress, reduce polyglutamine aggregation, and improve the deteriorated body bending rate caused by polyglutamine aggregation. Additionally, knockdown temporally in the post-developmental stage and spatially in the neuron display enhanced lifespan. Specifically, knockdown in glutamatergic or cholinergic neurons is sufficient to increase lifespan. Importantly, the lifespan extension by knockdown requires the activation of autophagy and AMPK pathways and reduced TOR signaling. Moreover, the RNA-seq data support our experimental findings and reveal potential novel downstream targets. Together, our data disclose the specific spatial and temporal conditions and the molecular mechanisms for knockdown-mediated longevity in . These findings may help the understanding and improvement of longevity in humans.